N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-nitro-3-trifluoromethylbenzamide | 945028-63-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-nitro-3-trifluoromethylbenzamide
• 英文别名: N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]-4-nitro-3-(trifluoromethyl)benzamide
• CAS: 945028-63-7
• 化学式: C₂₄H₁₇F₃N₆O₃
• 分子量: 494.433
• InChiKey: QUORKUMYBIURMD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-nitro-3-trifluoromethylbenzamide 在 铁粉 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 生成 4-amino-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Optimization of novel combi-molecules: Identification of balanced and mixed bcr-abl/DNA targeting properties

  摘要：

  Steps toward the identification of combi-molecules with strong abl tyrosine kinase (TK) inhibitory property and significant DNA damaging potential are described. The optimized combi-molecule 13a was shown to induce approximately twofold stronger abl TK inhibitory activity than Gleevec (TM) and high levels of DNA damage in chronic myelogenous leukemic cells. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.05.067
• 作为产物：
  描述：

  2-氨基-4-硝基甲苯 在 platinum(IV) oxide 、 氢气 、 硝酸 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 正丁醇 为溶剂， 反应 60.5h， 生成 N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-nitro-3-trifluoromethylbenzamide
  参考文献：
  名称：

  伊马替尼中间体和类似物合成的优化方法† ‡

  摘要：

  我们回顾了伊马替尼合成的经典合成方法，为制备一系列新的伊马替尼类似物提供了一种改进和优化的方法。所提出的方法有效地克服了某些有问题的步骤，节省了时间和劳力，提供了很高的产率和纯度，并具有用于合成许多类似物的潜力。所需胍盐4的形成，是伊马替尼合成的关键步骤之一，几乎是通过合适的苯胺3的盐酸盐与过量的熔融氰胺在没有任何溶剂的情况下反应而定量进行的。纯芳基胺中间体6a–d在亚当催化剂上用氢气将中间体嘧啶5a-d的硝基还原后，可以在很短的反应时间内定量获得。此外，这种优化方法的应用可以扩展到尼罗替尼及其类似物中间体的合成中。

  DOI：

  10.1039/c6ra09812f

文献信息

• Novel Imatinib Derivatives with Altered Specificity between Bcr–Abl and FMS, KIT, and PDGF Receptors
  作者：Konstantinos Skobridis、Maria Kinigopoulou、Vassiliki Theodorou、Emilia Giannousi、Alison Russell、Rakhee Chauhan、Roberta Sala、Nicola Brownlow、Serafim Kiriakidis、Jan Domin、Andreas G. Tzakos、Nick J. Dibb

  DOI：10.1002/cmdc.200900394

  日期：2010.1.4

  Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr–Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also

  伊马替尼是临床上重要的 ATP 类似物抑制剂，靶向细胞内 Abl 激酶和 PDGF 受体家族的酪氨酸激酶结构域。伊马替尼彻底改变了慢性粒细胞白血病的治疗，慢性粒细胞白血病是由致癌基因 Bcr-Abl 和某些含有 PDGF 受体家族致癌突变的实体瘤引起的。作为领先的激酶抑制剂，伊马替尼还提供了一个很好的模型系统来研究药物设计的变化如何影响生物活性，这是合理药物设计的重要考虑因素。在此我们报告了一系列新的伊马替尼衍生物，由于苯基和N的修饰，它们通常对 PDGF 受体家族具有更大的活性，而对 Abl 的活性较差-甲基哌嗪环。这些新化合物为针对治疗上重要的 PDGF 受体家族的进一步药物开发提供了一个平台，它们还提供了对具有改变生物活性的药物工程的深入了解。
• An optimized approach in the synthesis of imatinib intermediates and analogues
  作者：M. Kinigopoulou、M. Filippidou、M. Gogou、A. Giannousi、P. Fouka、N. Ntemou、D. Alivertis、C. Georgis、A. Brentas、V. Polychronidou、P. Voulgari、V. Theodorou、K. Skobridis

  DOI：10.1039/c6ra09812f

  日期：——

  classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt

  我们回顾了伊马替尼合成的经典合成方法，为制备一系列新的伊马替尼类似物提供了一种改进和优化的方法。所提出的方法有效地克服了某些有问题的步骤，节省了时间和劳力，提供了很高的产率和纯度，并具有用于合成许多类似物的潜力。所需胍盐4的形成，是伊马替尼合成的关键步骤之一，几乎是通过合适的苯胺3的盐酸盐与过量的熔融氰胺在没有任何溶剂的情况下反应而定量进行的。纯芳基胺中间体6a–d在亚当催化剂上用氢气将中间体嘧啶5a-d的硝基还原后，可以在很短的反应时间内定量获得。此外，这种优化方法的应用可以扩展到尼罗替尼及其类似物中间体的合成中。
• Optimization of novel combi-molecules: Identification of balanced and mixed bcr-abl/DNA targeting properties
  作者：Zakaria Rachid、Athanasia Katsoulas、Christopher Williams、Anne-Laure Larroque、James McNamee、Bertrand J. Jean-Claude

  DOI：10.1016/j.bmcl.2007.05.067

  日期：2007.8

  Steps toward the identification of combi-molecules with strong abl tyrosine kinase (TK) inhibitory property and significant DNA damaging potential are described. The optimized combi-molecule 13a was shown to induce approximately twofold stronger abl TK inhibitory activity than Gleevec (TM) and high levels of DNA damage in chronic myelogenous leukemic cells. (c) 2007 Elsevier Ltd. All rights reserved.
• <p>Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib</p>
  作者：Despoina Pantazi、Nikoleta Ntemou、Alexios Brentas、Dimitrios Alivertis、Konstantinos Skobridis、Alexandros D Tselepis

  DOI：10.2147/dddt.s211907

  日期：——

  Background: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy.Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties.Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I-IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed.Results: The novel analogues V-VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 mu M and 3.91 mu M, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds.Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.